Medical devices subject to triggered disintegration

ABSTRACT

The present invention provides medical devices comprised of ionically crosslinked polymer, especially, stents, catheter or cannula components, plugs, and constrictors. The medical devices of the present invention are prepared by treatment of ionically crosslinkable polymer compositions with crosslinking ion compositions to provide ionically crosslinked materials. 
     An important aspect of the present invention is that these medical devices can be disintegrated in-vivo at a desired time through the exposure of the medical device to a chemical trigger which generally is described as an agent that acts to displace the crosslinking ion in the ionically crosslinked material through binding or simple replacement with a non-crosslinking ion.

This application is a division, of application Ser. No. 08/128,952,filed Sep. 29, 1993, U.S. Pat. No. 5,531,716.

FIELD OF THE INVENTION

This invention relates to medical devices which can be caused to bedisintegrated in-vivo. More specifically the present invention relatesto novel medical device systems designed for triggered disintegrationcomprising one or more ionically crosslinkable polymers, one or morecrosslinking ions, and one or more agents which displace thecrosslinking ion.

BACKGROUND OF THE INVENTION

Medical devices are often used to facilitate the flow of material as,for example, in a ureteral stent used for drainage of urine from thekidney to the bladder, or in a vascular graft used to maintain bloodflow.

Typically these medical devices have been made from durable,non-biodegradable materials such as metals, polyurethanes,polyacrylates, etc. These non-biodegradable, non-dissolvable medicaldevices typically must be removed via an invasive procedure after theyhave served their purpose, or they remain in the body indefinitely. Forthose devices which remain in-vivo, there are often medicalcomplications such as inflammation and other foreign body responses.

Devices have also more recently been prepared from biodegradablematerials such as polyesters, polyanhydrides, and polyorthoesters. InU.S. Pat. No. 5,085,629, the use of a biodegradable polyester terpolymerof lactide, glycolide, and epsilon-caprolactone in a ureteral stent isdisclosed. In the '629 patent, biodegradable has been defined to includehydrolytic instability. These polymers undergo hydrolytic chain cleavagein the presence of water to form low molecular weight water solublespecies. The polyesters have been reported to undergo hydrolysisthroughout the thickness of the device simultaneously (homogeneoushydrolysis) while the polyanhydrides and polyorthoesters have beenreported to hydrolyse from the surface (heterogeneous hydrolysis). Thereare several problems inherent to devices manufactured with thesebiodegradable materials. There is a significant loss of strength in thedevice prior to any significant weight loss. These devices may undergofailure into large pieces which may occlude the vessel in which theyhave been deployed. Biodegradable devices which undergo surfacehydrolysis may eventually reach a thin skin configuration that may alsolead to vessel occlusion. Semicrystalline biodegradable materials havealso been shown to leave insoluble crystalline residuals in the body forvery long periods of time.

Polysaccharide--metal salt systems have been used for many years inbiomedical applications. In European Patent Application 0 507 604 A2, anionically crosslinked carboxyl-containing polysaccharide is used inadhesion prevention following surgery. The ionically crosslinkedpolysaccharide of this invention is left in-vivo. No attempt to dissolvethe material is made.

Hydrogels have been widely used in biomedical applications. In U.S. Pat.Nos. 4,941,870; 4,286,341 and 4,878,907, a hydrogel is used as a coatingon an elastomer base in a vascular prosthesis. This hydrogel remainsin-vivo. Kocavara et al in J. Biomed. Mater. Res. vol. 1, pp. 325-336(1967) have reported using an anastomosis ureteral prosthesis preparedfrom a poly(hydroxyethyl methacrylate) hydrogel reinforced withpolyester fibers. This prosthesis is designed to be left in vivo.

In U.S. Pat. Nos. 4,997,443 and 4,902,295, transplantable artificialpancreatic tissue is prepared from an alginic acid gel precursor, amatrix monomer, and pancreas cells with Ca²⁺ ions and a matrix monomerpolymerization catalyst. The calcium-alginic acid is used to providemechanical integrity to the mixture while the matrix monomer ispolymerized after which the calcium-alginic acid is removed with citratevia calcium chelation to leave a porous matrix. This use of the chelateto dissolve the calcium-alginic acid takes place in vitro. Thecalcium-alginic acid functions as a processing aid not as a structuralmember in the final artificial tissue device.

Polysaccharide--metal salt hydrogels have also been used to prepare tinygel capsules containing pancreatic islet cells for the production ofinsulin. These capsules have been shown by workers at the VeteransAdministration Wadsworth Medical Center to effectively control insulinlevels in diabetic dogs for two years (Scientific American, Jun. 1992,pp. 18-22). These capsules remain in vivo.

In U.S. Pat. No. 5,057,606 a method and article useful for preparingpolysaccharide hydrogels is disclosed. These foamed and non-foamedgelled articles are prepared by mixing together a first componentcomprising a suspension of a water insoluble di- or tri-valent metalsalt in an aqueous solution of a polysaccharide, with a second componentcomprising an aqueous solution of a water soluble acid optionally toinclude the water soluble polysaccharide. These gels remain in vivo.

The present invention eliminates the problems associated with thematerials discussed above. Hydrolytic instability is not relied upon tofacilitate dissolution. The devices of the present invention aredisintegrated upon demand through application of an agent, which acts toremove ionic crosslinking species, which may be anionic (mono or poly)or cationic (mono or poly) in nature, via binding or displacementmechanisms. As used herein, the term "disintegration" includes both thebreakdown of the device into small particulates as well as into watersoluble components. Triggered disintegration eliminates the timeuncertainty observed with bioerodible materials from one patient to thenext. Methods for triggered disintegration include administering ortriggering release of the disintegration agent through the diet,administering the agent directly onto the device in an aqueous solution,encapsulating the agent in the device, parenteral feeding, and enema.Disintegration occurs without significant swelling of the device.

SUMMARY OF THE INVENTION

The present invention provides a medical device comprising at least onemember selected from the group consisting of stents, catheter or cannulacomponents, plugs, and constrictors comprised of ionically crosslinkedpolymer. The medical devices of the present invention are prepared bytreatment of ionically crosslinkable polymer compositions withcrosslinking ion compositions to provide ionically crosslinkedmaterials. This treatment may involve crosslinking of an aqueoussolution of the ionically crosslinkable polymer component in a solutionof the crosslinking ion.

In another embodiment of the present invention, is found the novelcombination of a medical device comprising ionically crosslinked polymercombined with at least one body fluid selected from the group consistingof urine, bile, feces, blood and intestinal fluids. Another aspect ofthe present invention is a medical device comprising at least one memberselected from the group consisting of stents, catheter or cannulacomponents, plugs, and constrictors, wherein said medical devicecomprises at least one body fluid selected from the group consisting ofurine, bile, feces, blood and intestinal fluids and ionicallycrosslinked polymer.

Yet another embodiment of the present invention is a medical devicecomprising at least one member selected from the group consisting ofstents, catheter or cannula components, plugs, and constrictorscomprised of ionically crosslinked polymer and an agent that acts todisplace a crosslinking ion through binding or simple replacement with anon-crosslinking ion. The invention also comprises a method ofdisintegrating an in vivo medical device comprising treating said invivo medical device with at least one chemical trigger. These chemicaltriggers can comprise at least one agent that displaces a crosslinkingion.

The invention further comprises a method for medical treatment of humansand animals comprising introducing thereinto a medical device comprisingat least one member selected from the group consisting of stents,catheter or cannula components, plugs and constrictors wherein themedical device comprises ionically crosslinked polymer.

In another embodiment of the present invention, a method for medicaltreatment of humans and animals comprises introducing thereinto amedical device which comprises ionically crosslinked polymer, followedby disintegration of the medical device with a chemical trigger.

Still another aspect of the present invention is a medical devicecomprised of ionically crosslinked polymer hydrogel having a watercontent of less than 90%.

A method for making a medical device of the present invention comprisescrosslinking an ionically crosslinkable polymer with a crosslinking ion.wherein said medical device comprises at least one member selected fromthe group consisting of stents, catheter or cannula components, plugsand constrictors.

The devices prepared and equilibrated in accordance of the presentinvention at room temperature have excellent mechanical strength andelasticity, but it has been found that a higher temperature treatmentgreatly increases the stiffness and resistance to creep of the device.The equilibration of the device above room temperature, typicallybetween 40° C. and 100° C., not only results in improved mechanicalperformance, but allows a new shape to be set into the device.Densification of the device may occur during this heat treatment step.Unexpectedly, these shaped and densified devices maintain the new shapeand density upon return to room temperature. The densification andstrengthening of swollen ionically crosslinked compositions via heattreatment also constitutes an aspect of this invention.

One process for manufacturing the articles of the present inventioncomprises a method of making a tubular shaped article comprisingintroducing a solution comprising ionically crosslinkable polymerthrough a die to form a tube, simultaneously pumping a solutioncomprising crosslinking ion through the formed tube, and extruding theformed tube from said die into a solution comprising crosslinking ion.In this process the crosslinking step may involve shaping of the deviceas in wet spinning of a tubular device. Alternatively the device may beprepared by molding a latent crosslinking composition such as a one ortwo part reaction injection molding system. The term "tubular" as usedherein, includes not only cylindrical shaped devices having circularcross sections, but also devices having different cross sections as longas such articles have a hollow passageway such as that whichdistinguishes a tube from a rod.

Another process for the manufacture of the devices of the presentinvention would be conventional molding techniques such as reactioninjection molding wherein the ionically crosslinkable polymer and thecrosslinking ion are mixed and introduced into a mold to form an articleof the desired configuration.

In accordance with the present invention, the medical device may also beformed in-vivo. Such a method for medical treatment of humans andanimals comprises introducing thereinto an ionically crosslinkablepolymer and a crosslinking ion followed by crosslinking of said polymerto form a medical device selected from the group consisting of stents,catheter or cannula components, plugs, and constrictors, wherein saidmedical device comprises ionically crosslinked polymer.

Disintegration of the medical devices of this invention is achievedthrough exposure of the ionically crosslinked composition to agentswhich displace the crosslinking ion. Methods for introduction of theagent include: introduction through or triggered release through thediet of the patient, through parenteral feeding, introduction of asolution directly onto the device or through release of encapsulatedagent in the device itself, or through an enema. The medical devices ofthe present invention are thereby removed safely from the body in theform of water soluble components through exposure to agents thatdisplace the crosslinking ion. Disintegration occurs with minimumswelling of the device.

The medical devices of the present invention that comprise ionicallycrosslinked polymer are especially useful in various systems in the bodyof animals or humans, including, but not limited to thegastrointestinal, urogenital, cardiovascular, lymphatic,otorhinolaryngological, optical, neurological, integument and muscularsystems.

Still another aspect of the present invention is that these medicaldevices which comprise ionically crosslinked polymer are sterilizable attemperatures of at least 121° C.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a wet-spinning apparatus used in the practice of thepresent invention.

FIG. 2 shows the wet-spinning die that is a part of the apparatus shownin FIG. 1.

FIG. 3 shows a reaction injection molding set up for manufacture ofmedical devices of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The medical devices, of the present invention are prepared by treatmentof ionically crosslinkable polymers, with crosslinking ions to provideionically crosslinked materials.

The ionically crosslinkable polymers may be anionic or cationic innature and may include but are not limited to carboxylic, sulfate, andamine functionalized polymers such as polyacrylic acid, polymethacrylicacid, polyethylene amine, polysaccharides such as alginic acid, pectinicacid, carboxy methyl cellulose, hyaluronic acid, heparin, chitosan,carboxymethyl chitosan, carboxymethyl starch, carboxymethyl dextran,heparin sulfate, chondroitin sulfate, cationic guar, cationic starch,and their salts. Preferred ionically crosslinkable polymers are alginicacid, pectinic acid, carboxymethyl cellulose, hyaluronic acid, chitosan,and their salts. Most preferred ionically crosslinkable polymers arealginic acid, pectinic acid, and hyaluronic acid and their salts. Aspreviously noted, the ionically crosslinkable polymers employed in thepresent invention are categorized as ionically crosslinkable anionicpolymers and ionically crosslinkable cationic polymers. Among theionically crosslinkable anionic polymers that may be employed arepolyacrylic acid, polymethacrylic acid, alginic acid, pectinic acid,carboxy methyl cellulose, hyaluronic acid, heparin, carboxymethylstarch, carboxymethyl dextran, heparin sulfate, and chondroitin sulfate.Among the ionically crosslinkable cationic polymers that may be employedare chitosan, cationic guar, cationic starch and polyethylene amine.

The crosslinking ions are generally classified as anions or cations.Appropriate crosslinking ions include but are not limited to cationscomprising an ion selected from the group consisting of calcium,magnesium, barium, strontium, boron, beryllium, aluminum, iron, copper,cobalt, lead, and silver ions, and anions selected from the groupconsisting of phosphate, citrate, borate, succinate, maleate, adipateand oxalate ions. More broadly the anions are derived from polybasicorganic or inorganic acids. Preferred crosslinking cations are calcium,iron, and aluminum ions. The most preferred crosslinking cations arecalcium and iron ions. The most preferred crosslinking anion isphosphate.

Appropriate agents that displace a crosslinking ion include, but are notlimited to ethylene diamine tetraacetic acid, ethylene diaminetetraacetate, citrate, organic phosphates, such as cellulose phosphate,inorganic phosphates, as for example, pentasodium tripolyphosphate, monoand di-basic potassium phosphate, sodium pyrophosphate, and phosphoricacid, trisodium carboxymethyloxysuccinate, nitrilotriacetic acid, maleicacid, oxalate, polyacrylic acid, sodium, potassium, calcium andmagnesium ions. Preferred agents are citrate, inorganic phosphates,sodium, potassium and magnesium ions. The most preferred agents areinorganic phosphates and magnesium ions.

The devices may optionally include water, other additives for medicaltreatment such as antiseptics, antibiotics, anticoagulants, ormedicines, and additives for mechanical property adjustment.

Linear device or pre-device configurations such as fibers, rods, tubesor ribbons can be manufactured in accordance with the present inventionby using a spinning device in which a solution of the ionicallycrosslinkable polymer is forced through a shaping die into acrosslinking bath containing the crosslinking ions. If the ionicallycrosslinkable polymer solution is aqueous, the product aftercrosslinking is typically described as a hydrogel. The hydrogel may beused as made or further given a three dimensional shape throughtreatment in a crosslinking solution after being forced into the desiredshape. After equilibration the hydrogel will retain the new threedimensional shape. The device may be used in its hydrogel form or in adehydrated form. During dehydration the three dimensional shape isretained.

More complex shaped devices can be made using a one or two part reactioninjection molding composition. These molding compositions typicallycontain the ionically crosslinkable polymer in solution, thecrosslinking ion in an insoluble or slowly soluble form and additives tocause dissolution of the crosslinking ion. When the crosslinking iondissolves and dissociates the ionically crosslinkable polymer solutiongels. This gel (or hydrogel if the solvent is water) may be used as madeor further developed, crosslinked, and shaped by soaking in a solutionof a crosslinking ion. Dissolution of the crosslinking ion to form thegel may be effected by using a two part molding system in which thesecond component contains an acid or pre-acid such as a cyclic lactonewhich lowers the pH and solubilizes the previously insolublecrosslinking ion.

The device may then be placed into the body for use. After use thedevice may be disintegrated in-vivo via exposure to an aqueous solutionof an agent which displaces the crosslinking ion.

These medical devices are useful in medical applications where theremoval of the standard non-disintegratable medical device involvespatient discomfort and/or expense and in applications where a temporarydevice is therapeutically desirable. Examples of useful applications forthese devices include ureteral, urethral, bilial, ileal and pyloricstents. In these applications current state of the art stents must beremoved by a second invasive procedure at great expense and patientdiscomfort. The devices of this invention facilitate removal, leading toreduced patient discomfort and expense. The medical devices of thisinvention are also useful in cardiovascular, lymphatic, neurological,integumental, skeletal, muscular, optical, otorhinolaryngological, oral,gastrointestinal and urogenital applications where controlleddisintegration of the ionically crosslinked portion of the device isefficacious and in surgical procedures where a device is neededtemporarily such as a cellular scaffold after which removal bydissolution is preferred. Other medical device applications may includeadhesion prevention devices, drainage devices as in ear or sinus tubes,release devices in dental and medical applications, wound care as in thetreatment of bed sores, temporary scaffold for bone, osteophiliccoatings, neural growth guides, temporary stent for anastomosis, shapeddelivery devices, hemostats, surgical sponges, hydrocephalus shunt,dialysis tubing, instrument coatings, patches for delivery systems,ostomy bags, form-fit wound care devices which are gelled on thepatient, temporary plug, syringe deliverable temporary fill for aneurismrepair, artificial skin, dental socket filler having therapeuticadditives, temporary vena cava filter device, capsule for delivery ofvena cava filter devices, deep vein thrombosis filter for orthopedicapplications, dissolvable enteral feeding tube, enteral plugs, andhiatal hernia stents. Any of these devices may also act to releasemedicines, nutrients and the like.

The present invention eliminates the problems associated with the priorart materials. Hydrolytic instability is not used to facilitatedissolution. These devices are disintegrated upon demand throughapplication of an agent which displaces the crosslinking ion into thedevice. Triggered disintegration eliminates the time uncertaintyobserved with bioerodible materials from one patient to the next.Methods for triggered disintegration include administering or triggeringrelease of the agent through the diet, administering the agent directlyonto the device in an aqueous solution, encapsulating the agent in thedevice, parenteral feeding, and enema. Disintegration occurs withoutsignificant swelling of the device.

In FIG. 1 is shown a wet spinning apparatus used to make the medicaldevices of the present invention. A syringe pump 1 is shown for pumpingthe contents of syringe 3 and syringe 4. Syringe 3 is filled with theionically crosslinkable polymer and syringe 4 is filled with thecrosslinker, usually a crosslinking ion solution. Syringe 3 is connectedto wet spinning die 6 into which is a side tube 7 connected to syringe4. A crosslinking bath 5 contains the crosslinking ion solution which isrecirculated through tube 8 by peristaltic pump 2.

In FIG. 2 is shown wet spinning die 6 having an end 9 into which entersthe ionically polymerizable polymer and an end 10 out of which comes anarticle comprising the reaction product of the polymer and crosslinkingion. The crosslinking ion enters through side tube 7 so that as a tubeis formed in the wet spinning die, the polymer is contacted with thecrosslinking ion on the inside and outer surfaces of the tube.

In FIG. 3 is shown a reaction injection molding apparatus used to makemedical devices of the present invention having a syringe pump 21connected to syringe 22 which contains an ionically crosslinkablepolymer and an insoluble salt comprising a crosslinking ion and tosyringe 23 which contains an ionically crosslinkable polymer and a pHadjuster. The contents of syringes 22 and 23 are injected into y-tube 24and pass into static mixer 25. Both y-tube 24 and static mixer 25 aresilicone tubing. The contents of the static mixer 25 then travel fromstatic mixer end 26 into port 27 of mold 30 having a tubular shapedcavity 29 and a rod 28 positioned so that a tubular shaped device ismolded and gels. The gelled tubular shaped device may then be placed ina solution comprising crosslinking ion until a sufficiently crosslinkedpolymer is made.

The invention is further illustrated by the following examples.

EXAMPLE 1

To 95.10 grams of distilled water was added 5.005 grams of sodiumalginic acid (Sigma, medium molecular weight, macrocystis pyrifera)which were mixed until uniform (approximately 1 hour), heated to 90° C.for 45 minutes, cooled to room temperature and then centrifuged toremove trapped air. The sodium alginic acid solution was then used tofill a 30 cc syringe which was attached to the wet spinning dieillustrated in FIG. 1. The syringe and die were hooked up as shown inFIG. 1 to a syringe pump, crosslinking solution syringe containing 10%by weight CaCl₂ dihydrate in water, and a peristaltic pump feedcontaining 10% by weight CaCl₂ dihydrate in water. The syringe pump wasused to wet spin a tube of sodium-alginic acid into a crosslinking bathcontaining 10% by weight CaCl₂ dihydrate in water. After the tube hadbeen spun the peristaltic pump was turned on to maintain the flow ofcoagulant solution through the tube. After 30 minutes the tube wasremoved from the crosslinking bath and placed in a 4% by weight CaCl₂dihydrate solution in water. The tube was left in this solution for 24hours.

EXAMPLE 2

Sections of tube prepared as in Example 1 were immersed in the followingaqueous solutions: a) 0.5% monobasic potassium phosphate and 0.5%dibasic potassium phosphate, and b) 1% sodium tripolyphosphate,respectively, and left to stand overnight. The tubes in vials a and bhad broken up and disintegrated overnight.

EXAMPLE 3

Tubing prepared as in Example 1 was placed over a copper wire which wasthen bent at both ends to form pigtails. The tubing and wire were thenplaced into a 4% by weight CaCl₂ dihydrate solution in water which washeated to 90° C. for 12 hours. After cooling the solution to roomtemperature the tubing and wire were removed from the solution, the wirerestraightened and the tubing removed from the wire. The tubing hadretained the shape of the wire, now having pigtails on each end andexhibited a decrease in wall thickness.

EXAMPLE 4

A short section of tube cut from tubing which had been heat shaped as inExample 3 was then immersed in a 0.50% by weight sodium citrate solutionin water. The tube disintegrated fully in less than 6 hours.

EXAMPLE 5

Approximately 15 grams of a 5% by weight sodium alginic acid solution inwater (prepared as in Example 1) was loaded into a 30 cc syringe. Thesyringe and die were hooked up as shown in FIG. 1 to a syringe pump,crosslinking solution syringe containing 10% by weight Al₂ (SO₄)₃ ·18H₂O in water, and a peristaltic pump feed containing 10% by weight Al₂(SO₄)₃ ·18H₂ O in water. The syringe pump was used to wet spin a tube ofsodium alginic acid into a crosslinking bath containing 10% by weightAl₂ (SO₄)₃ ·18H₂ O in water. After the tube had been spun theperistaltic pump was turned on to maintain the flow of coagulantsolution through the tube. After 20 minutes the tube was removed fromthe crosslinking bath and placed in a 4% by weight Al₂ (SO₄)₃ ·18H₂ Osolution in water. The tube was left in this solution for 24 hours. Thetube was then heated to 90° C. in the 4% Al₂ (SO₄)₃ ·18H₂ O solution inwater for 16 hours. A 1/4" length of heat treated tube was then shown todissolve and fall apart in a 0.50% by weight sodium tripolyphosphate inwater solution overnight.

EXAMPLE 6

Approximately 2 cc of a 5% by weight sodium alginic acid solution inwater prepared as in Example 1 was loaded into a 10 cc syringe fromwhich it was spun into a 4% by weight solution of FeCl₃ in water. Thesolution coagulated immediately to form a continuous fiber. Aftersitting overnight in the FeCl₃ solution, the fiber was heated in the 4%by weight solution of FeCl₃ in water for 16 hours at 90° C., then apiece of the fiber was immersed in a 0.50% sodium tripolyphosphatesolution in water. The fiber disintegrated overnight.

EXAMPLE 7

A 5% by weight sodium alginic acid solution in water prepared as inExample 1 was spun from a 10 cc syringe into a 4% by weight SrCl₂ ·6H₂ Osolution in water. The alginic acid solution gelled immediately to forma fiber. The fiber was left in the crosslinking solution overnight. Thefollowing day the fiber was heated for 16 hours at 90° C. in the samecrosslinking solution. Short sections of the heat treated fiber wereimmersed in a 0.5% by weight sodium tripolyphosphate in water solutionand a 0.5% by weight sodium citrate in water solution. The fiber in thesodium tripolyphosphate solution disintegrated within 3 hours. The fiberin the sodium citrate solution disintegrated overnight.

EXAMPLE 8

0.010 grams of sodium hyaluronate (Chisso Corp, lot# 700910, MW1.35X10⁶) were added to 0.99 grams of a 5% by weight sodium alginic acidsolution which had been prepared as in example 1. The solution was mixedwith a spatula until the hyaluronate had dissolved and the solution wasuniform. The solution was then transferred to a 2.5 cc glass syringe. An18 gauge, 1.5" long needle was attached to the glass syringe and thesample was spun into a 10% by weight CaCl₂ ·2H₂ O solution in water. Thesample gelled quickly to form a fiber. The fiber was left in thecrosslinking solution for 1 hour. The fiber was then transferred to a 4%aqueous solution of CaCl₂ ·2H₂ O and left overnight. The fiber was thenheated in the 4% aqueous solution of CaCl₂ ·2H₂ O for 16 hours. Thefiber was then shown to disintegrate and dissolve in a 0.5% aqueoussolution of sodium tripolyphosphate overnight.

EXAMPLE 9

1.25 grams of pectinic acid (GENU® pectinic acid Hercules Incorporated,LM 1912 CSZ) were added to 47.5 grams of distilled water while mixing.Mixing was continued for 15 minutes after which 1.25 grams of sodiumalginic acid (Sigma, medium molecular weight) were added. The mixturewas mixed for another 30 minutes then centrifuged to remove trapped air.Approximately 2 cc of the solution were loaded into a 2.5 cc syringe.The solution was spun directly from the syringe into a 10% CaCl₂ ·2H₂ Osolution in water. The material gelled immediately in the form of afiber. The fiber was left in the crosslinking solution for 20 minutesthen the CaCl₂ ·2H₂ O was diluted down to 4% by the addition ofdistilled water. The sample was stored in this 4% solution overnight. Asmall piece of the fiber was shown to dissolve overnight in a 0.5%sodium tripolyphosphate solution in water.

EXAMPLE 10

A 2.9% by weight sodium hyaluronate solution in water was prepared byadding 0.10 grams of sodium hyaluronate (Chisso Corporation) to 3.40grams of distilled water. 0.73 grams of a 3% aqueous solution of FeCl₃were decanted on top of the sodium hyaluronate solution. The hyaluronatesolution began to gel immediately. After 3 hours a small piece of thegel was removed and immersed in a 0.5% aqueous solution of sodiumtripolyphosphate. The gel disintegrated overnight.

EXAMPLE 11

0.82 grams of heparin (Fluka) and 0.83 grams of distilled water wereweighed into a 5 ml vial, stirred until the heparin dissolved thencentrifuged to remove trapped air. An equal volume (approximately 1.6cc) of a 3% by weight FeCl₃ solution in water was then decanted into the5 ml vial on top of the heparin solution. After sitting overnight atroom temperature the heparin solution had gelled. This gel was shown todissolve fully in a 0.5% sodium tripolyphosphate solution in waterwithin a few hours.

EXAMPLE 12

4.00 grams of Mannugel DMB (Kelco International Limited) were added to76.00 grams of distilled water while stirring. The sample was stirredfor 1 hour at room temperature after which it was heated for 1 hour at90° C. The sample was then centrifuged to remove trapped air.Approximately 30 cc of the Mannugel solution was transferred to a 30 ccsyringe. The syringe was attached to a tube die as in FIG. 1 to asyringe pump, crosslinking solution syringe containing 10% by weightCaCl₂ dihydrate in water, and a peristaltic pump feed containing 10% byweight CaCl₂ dihydrate in water. The syringe pump was used to wet spin atube of sodium-alginic acid into a crosslinking bath containing 10% byweight CaCl₂ dihydrate in water. After the tube had been spun theperistaltic pump was turned on to maintain the flow of crosslinkingsolution through the tube. After 20-30 minutes the tube was removed fromthe crosslinking bath and placed in a 4% by weight CaCl₂ dihydratesolution in water. The tube was left in this solution overnight. A pieceof the tubing was then heat treated at 90° C. for 16 hours in the 4% byweight CaCl₂ dihydrate solution in water. A piece of the heat treatedtube was then immersed in a 0.5% by weight sodium tripolyphosphatesolution in water. After sitting overnight the tube had fallen apart anddisintegrated.

EXAMPLE 13

5.0 grams of pectinic acid (GENU® pectinic acid Hercules Inc., LM 1912CSZ) were added to 45.0 grams of distilled water while mixing. Another16.62 grams of distilled water were added and mixed until uniform. Thesolution was centrifuged to remove trapped air. Approximately 2 cc ofthe solution were loaded into a 2.5 cc syringe. The solution was spunthrough a 1.5" long 18 gauge needle into a 10% CaCl₂ ·2H₂ O in watersolution. The fiber gelled immediately. The fiber was left in thecrosslinking bath for 45 minutes after which it was transferred to a 4%CaCl₂ ·2H₂ O in water solution and left overnight. The fiber in the 4%CaCl₂ 2H₂ O water solution was then heated to 90° C. for 16 hours. Apiece of the fiber was then shown to fully dissolve in a 0.5% sodiumtripolyphosphate solution in water.

EXAMPLE 14

2.40 grams of CaHPO₄ were dispersed in 76.63 grams of distilled water.4.00 grams of sodium alginic acid (Sigma, medium molecular weight) werethen added to this suspension while mixing. After mixing until uniformthe solution/suspension was heated to 90° C. for 20 minutes, mixed in aAmerican Brand Ultrasonic Cleaner Bath for thirty minutes, leftovernight at room temperature, then centrifuged to remove trapped air. Asecond solution was prepared by mixing 0.30 grams of D-gluconic acidlactone (Sigma) into 9.70 grams of a 5% solution of sodium alginic acidin water. Parts 1 and 2 were then loaded into separate 10 cc syringes,fitted as in FIG. 3. The syringe pump was used to force the twosolutions through the static mixer into a mold designed to produce a 10"long tube having 0.12" outer diameter and 0.04" inner diameter. After1.5 hours the mold was opened and the gelled tube removed. The tube wasplaced into a 4% by weight CaCl₂ ·H₂ O solution in water. After sittingovernight a piece of copper wire was inserted into the tube, shaped suchthat both ends formed pigtails, then heat treated at 90° C. for 16hours. The heat shaped tube was then removed from the copper wire. Thetube retained the pigtail shape at both ends. A piece of the tube wasimmersed into a 0.50% solution of sodium tripolyphosphate in water. Thetube fell apart and disintegrated overnight.

EXAMPLE 15

About 0.5 ml of a 25% by weight solution of sodium polyacrylic acid(Polysciences, MW of 140,000) were added to about 5 ml of a 4% by weightcalcium chloride dihydrate solution in water. The polyacrylic acidformed a gel overnight. A small piece of this gel was shown to dissolveovernight in 10 cc of 0.5% sodium tripolyphosphate.

What is claimed is:
 1. An in vivo medical device comprising at least onemember selected from the group consisting of stents, catheters,cannulas, plugs, and constrictors, wherein said medical device comprisesionically crosslinked polymer, has sufficient mechanical strength toserve as a stent, catheter, cannula, plug or constrictor, and is capableof being in contact with at least one body fluid selected from the groupconsisting of urine, bile, feces, blood and intestinal fluids.
 2. Themedical device of claim 1 wherein said ionically crosslinked polymercomprises at least one polymer made from one or more members selectedfrom the group consisting of carboxylic, sulfate and aminefunctionalized polymers.
 3. The medical device of claim 1 wherein saidionically crosslinked polymer comprises at least one polymer made fromat least one polysaccharide.
 4. The medical device of claim 1 whereinsaid ionically crosslinked polymer comprises at least one polymer madefrom at least one ionically crosslinked cationic polymer.
 5. The medicaldevice of claim 4 wherein said ionically crosslinked cationic polymercomprises at least one polymer made from one or more members selectedfrom the group consisting of chitosan, cationic guar, cationic starchand polyethylene amine.
 6. The medical device of claim 1 wherein saidionically crosslinked polymer is crosslinked by a crosslinking ion whichcomprises one or more anions.
 7. The medical device of claim 6 whereinsaid one or more anions are selected from the group consisting ofphosphate, citrate, borate, succinate, maleate, adipate and oxalateions.
 8. The medical device of claim 6 wherein said one or more anionsis phosphate ion.
 9. The medical device of claim 1 wherein saidionically crosslinked polymer is crosslinked by a crosslinking ion whichcomprises one or more cations.
 10. The medical device of claim 9 whereinsaid one or more cations are selected from the group consisting ofcalcium, magnesium, barium, strontium, boron, beryllium, aluminum, iron,copper, cobalt, lead, and silver ions.
 11. The medical device of claim 9wherein said one or more cations are selected from the group consistingof calcium, iron, and aluminum ions.
 12. The medical device of claim 9wherein said one or more cations is calcium ion.
 13. The medical deviceof claim 1 wherein said ionically crosslinked polymer comprises at leastone polymer made from at least one ionically crosslinked anionicpolymer.
 14. The medical device of claim 13 wherein said ionicallycrosslinked anionic polymer comprises at least one polymer made from oneor more members selected from the group consisting of alginic acid,pectinic acid, carboxymethyl cellulose, hyaluronic acid and saltsthereof.
 15. The medical device of claim 13 wherein said ionicallycrosslinked anionic polymer comprises at least one polymer made from oneor more members selected from the group consisting of polyacrylic acid,polymethacrylic acid alginic acid, pectinic acid, carboxy methylcellulose, hyaluronic acid, heparin, carboxymethyl starch, carboxymethyldextran, heparin sulfate, and chondroitin sulfate, and salts thereof.16. The medical device of claim 15 wherein said ionically crosslinkedpolymer is crosslinked by a crosslinking ion which comprises barium. 17.The medical device of claim 15 wherein said ionically crosslinkedpolymer is crosslinked by a crosslinking ion which comprises strontium.18. The medical device of claim 15 wherein said ionically crosslinkedpolymer is crosslinked by a crosslinking ion which comprises copper. 19.The medical device of claim 15 wherein said ionically crosslinkedpolymer is crosslinked by a crosslinking ion which comprises copper. 20.The medical device of claim 1, further comprising an additive formedical treatment selected from the group consisting of antiseptics,antibiotics, anticoagulants, nutrients, and medicines.
 21. The medicaldevice of claim 20, further comprising a disintegration agent andwherein said medicine is released upon disintegration of said ionicallycrosslinked polymer.
 22. The medical device of claim 21, wherein thedisintegration agent is encapsulated.
 23. The medical device of claim21, wherein said disintegration agent comprises at least one agent thatdisplaces a crosslinking ion.